Linker Hydrophilicity Modulates the Anticancer Activity of RGD-Cryptophycin Conjugates
| Autor: | Isabell Kemker, Eduard Figueras, Norbert Sewald, Carmela Michalek, Michele Anselmi, Luca Gentilucci, Adina Borbély |
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| Přispěvatelé: | Anselmi M., Borbely A., Figueras E., Michalek C., Kemker I., Gentilucci L., Sewald N. |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
integrin
Antineoplastic Agents 010402 general chemistry 01 natural sciences Catalysis antitumor agents chemistry.chemical_compound Cell Line Tumor Depsipeptides Humans small molecule drug conjugates Cytotoxicity Full Paper 010405 organic chemistry Organic Chemistry beta-glucuronidase General Chemistry Full Papers Ligand (biochemistry) Glucuronic acid 3. Good health 0104 chemical sciences Drug Liberation chemistry Cryptophycin antitumor agent Drug delivery Biophysics Antimitotic Agent Drug Delivery Linker Hydrophobic and Hydrophilic Interactions Oligopeptides Conjugate |
| Zdroj: | Chemistry (Weinheim an Der Bergstrasse, Germany) |
| DOI: | 10.1002/chem.202003471 |
| Popis: | Most anticancer agents are hydrophobic and can easily penetrate the tumor cell membrane by passive diffusion. This may impede the development of highly effective and tumor‐selective treatment options. A hydrophilic β‐glucuronidase‐cleavable linker was used to connect the highly potent antimitotic agent cryptophycin‐55 glycinate with the αvβ3 integrin ligand c(RGDfK). Incorporation of the self‐immolative linker containing glucuronic acid results in lower cytotoxicity than that of the free payload, suggesting that hydrophilic sugar linkers can preclude passive cellular uptake. In vitro drug‐release studies and cytotoxicity assays demonstrated the potential of this small molecule–drug conjugate, providing guidance for the development of therapeutics containing hydrophobic anticancer drugs. Sweet specificity: A β‐glucuronidase‐responsive linker was chosen to minimize the hydrophobicity and connect the potent antimitotic agent cryptophycin‐55 glycinate to the αvβ3 integrin ligand c(RGDfK). The presence of a hydrophilic carbohydrate linker significantly decreased the cytotoxicity of RGD–cryptophycin conjugates relative to the free drug. The conjugate efficiently releases the drug upon linker cleavage by β‐glucuronidase. |
| Databáze: | OpenAIRE |
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